Serine/arginine-rich (SR) proteins are important regulators of mRNA splicing. Several postsplicing activities have been described for a subset of shuttling SR proteins, including regulation of mRNA export and translation. Using the fibronectin gene to study the links between signal-transduction pathways and SR protein activity, we show that growth factors not only modify the alternative splicing pattern of the fibronectin gene but also alter translation of reporter messenger RNAs in an SR protein–dependent fashion, providing two coregulated levels of isoform-specific amplification. These effects are inhibited by specific small interfering RNAs against SR proteins and are mediated by the AKT kinase, which elicits opposite effects to those evoked by overexpressing SR protein kinases Clk and SRPK. These results show how SR protein activity is modified in response to extracellular stimulation, leading to a concerted regulation of splicing and translation.
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We thank M. de la Mata, J.P. Fededa, I. Schor, E. Petrillo and M. Alló for encouraging discussions as well as V. Buggiano and R. Fernandez for technical help. This work was supported by grants from Fundación Antorchas, Universidad de Buenos Aires, Agencia Nacional de Promoción Científica y Tecnológica and Consejo de Investigaciones Científicas y Técnicas (CONICET). M.B., F.P., T.T., M.J.M. and D.W. are recipients of doctoral fellowships from the CONICET. A.S., J.P.M, A.R.K. and O.A.C. are investigators of the CONICET. A.R.K. is an International Research Scholar of the Howard Hughes Medical Institute. We also acknowledge support from the Medical Research Council (J.F.C.) and the Caledonian Research Foundation (J.R.S.).
The authors declare no competing financial interests.
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Blaustein, M., Pelisch, F., Tanos, T. et al. Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nat Struct Mol Biol 12, 1037–1044 (2005). https://doi.org/10.1038/nsmb1020
Identification of splice regulators of fibronectin-EIIIA and EIIIB by direct measurement of exon usage in a flow-cytometry based CRISPR screen
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